Endometrial effects of a tissue selective estrogen complex containing bazedoxifene/conjugated estrogens as a menopausal therapy

MENOPAUSE Endometrial effects of a tissue selective estrogen complex containing bazedoxifene/conjugated estrogens as a menopausal therapy James H. Pickar, M.D., a I-Tien Yeh, M.D., b Gloria Bachmann, M.D., c and Leon Speroff, M.D. d a Wyeth Research, Collegeville, Pennsylvania; b University of Texas Health Science Center, San Antonio, Texas; c Robert Wood Johnson University Hospital, New Brunswick, New Jersey; and d Oregon Health and Science University, Portland, Oregon Objective: To evaluate the endometrial safety of a tissue selective estrogen complex (TSEC; pairing of a selective estrogen receptor modulator [SERM] with estrogens) composed of bazedoxifene/conjugated estrogens (/CE) in postmenopausal women. Design: Randomized, double-blind, multicenter, placebo- and active-controlled, phase 3 study (Selective estrogen Menopause And Response to Therapy [SMART]-1). Setting: Outpatient clinical. Patient(s): Healthy, postmenopausal women (n ¼ 3,397) age 40 75 with an intact uterus. Intervention(s): Single tablets of (10, 20, or 40 mg) combined with CE (0.625 or 0.45 mg); raloxifene (60 mg); or placebo daily for 2 years. Main Outcome Measure(s): Incidence of endometrial hyperplasia at 12 months in the efficacy evaluable population. Result(s): Treatment with (20 or 40 mg)/ce (0.625 or 0.45 mg) was associated with low rates (<1%) of endometrial hyperplasia that were not significantly different from those reported with placebo over 24 months. Endometrial thickness with (20 or 40 mg)/ce (0.625 or 0.45 mg) was not significantly different from that with placebo. Conclusion(s): When combined with CE (0.625 mg or 0.45 mg), was the lowest effective dose that prevented endometrial hyperplasia over 2 years of study, creating the possibility for a new, progestin-free menopausal therapy. (Fertil Steril Ò 2009;92:1018 24. Ó2009 by American Society for Reproductive Medicine.) Key Words: B azedoxifene, conjugated estrogens, endometrium, hyperplasia, tissue-selective estrogen complex, TSEC The first two observational studies reporting an association of endometrial cancer with unopposed estrogen therapy (no progestin) Received October 20, 2008; revised April 22, 2009; accepted May 7, 2009; published online July 26, 2009. Supported by Wyeth Research, Collegeville, Pennsylvania. These data were presented at the following meetings: Annual Meeting of the Endocrine Society (ENDO), Toronto, Canada June 1 2, 2007; Triennial Amsterdam Menopause Symposium, June 19 21, Amsterdam, the Netherlands; 63rd Annual Meeting of the American Society for Reproductive Medicine, October 13 17, 2007, Washington, DC; the Federacion Latino Americana de Sociedades Climaterio y Menopausia Congreso, October 17 19, 2007, Quito, Ecuador; and the 12th World Congress on the Menopause, May 19 23, 2008, Madrid, Spain. J.H.P. is an employee of Wyeth Research. I-T.Y. is a pathologist who consulted for Wyeth Research to read endometrial biopsies. G.B. received grant/research support from and is a consultant to Astellas, Wyeth, Bayer, Duramed, Pfizer, Boehringer-Ingelheim, Roche, Merck, Quat Rx, Bionovo, GlaxoSmithKline, Femme Pharma, Hormos, Covance, Novartis, Johnson & Johnson, Boston Scientific, Novo Nordisk, Proctor & Gamble, and Xanodyne. L.S. is a consultant for Warner-Chilcott. Clinical trial registration information is available at http://www.clinical trials.gov, NCT00675688. Reprint requests: James H. Pickar, M.D., Women s Health, Clinical Research and Development Wyeth Research, P.O. Box 8299, Philadelphia, PA 19101 (TEL: 484-865-5583; FAX: 484-865-0076; E-mail: pickarj@wyeth.com). were published in 1975 (1, 2). Since then, endometrial cancer and endometrial hyperplasia have become well known potential consequences of unopposed estrogen therapy. Soon after those initial reports, clinicians began prescribing lower doses of estrogens. For example at the time, conjugated estrogens (CEs) were frequently prescribed at doses of 1.25 mg and greater, which are rarely prescribed today. The addition of progestin to estrogen therapy was also found to prevent the endometrial hyperplasia observed with estrogen alone. Doses and regimens of medroxyprogesterone acetate (MPA) adequate to prevent the endometrial hyperplasia observed with CE were first reported in 1994 (3). To date, addition of a progestin has been the pharmacologic intervention clinically utilized to prevent estrogen-induced endometrial stimulation. An alternate approach to protecting the endometrium from estrogen stimulation in menopausal therapy is a tissue-selective estrogen complex (TSEC), the partnering of a selective estrogen receptor modulator (SERM) with estrogens. With such a strategy, endometrial protection could be achieved through modulation of the estrogen receptor. The clinical profile of a TSEC would be based on the blended tissue-selective activities of both SERMs and estrogens. The ideal estrogen-serm combination would have the positive attributes of both components without or with fewer of their undesired effects. An appropriate TSEC would alleviate 1018 Fertility and Sterility â Vol. 92, No. 3, September 2009 0015-0282/09/$36.00 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2009.05.094

hot flushes, treat vulvar and vaginal atrophy, and protect against postmenopausal bone loss without stimulating the endometrium or the breast. Importantly, not all estrogen-serm combinations will be effective; for example, endometrial stimulation was reported with estradiol-raloxifene combinations (4, 5). Bazedoxifene () is a SERM that has not been shown to stimulate the endometrium in either preclinical or clinical studies. In preclinical studies, was associated with consistently lower uterine wet weight, compared with other SERMs, and maintained bone mass (6, 7). In a phase 2 clinical study, all doses of evaluated were well tolerated and did not stimulate the endometrium (8). In fact, higher doses of antagonized endometrial activity, as evidenced by significantly reduced endometrial thickness and uterine bleeding compared with placebo (8). Further preclinical investigation indicated that antagonized an estradiol-induced increase in uterine wet weight of ovariectomized mice (9). Based on these favorable data of on the endometrium in conjunction with the ability of CE to relieve hot flushes, improve vaginal heath, and possibly increase BMD to a greater extent than a SERM alone, a TSEC containing and CE was designed as a potential new combination menopausal therapy. The primary objective of this study was to evaluate the endometrial safety of a TSEC composed of various doses of and CE. In addition, this study will help determine the lowest effective dose of required for endometrial protection when combined with CE. MATERIALS AND METHODS The Selective estrogen Menopause And Response to Therapy-1 (SMART-1) trial was a 2-year, outpatient, randomized, double-blind, placebo- and activecontrolled, phase 3 study conducted at 94 sites in the United States, Europe, and Brazil (NCT00675688). At each site, the study was approved by an independent ethics committee or institutional review board. Subjects were recruited from April 3, 2002 to December 31, 2003. Based on a randomization schedule generated by Wyeth Research, subjects were allocated to one of eight treatment groups through the use of a computerized randomization and enrollment interactive voice recognition system. Treatment groups included: (10, 20, or 40 mg) each combined with CE (0.625 or 0.45 mg); raloxifene (60 mg); or placebo. Raloxifene was included as a reference for nonhyperplastic endometrial changes. To maintain blinding, /CE and raloxifene were provided as single tablets, which were over-encapsulated to match placebo capsules. Subjects were to take one tablet orally at approximately the same time each day for 2 years. Generally healthy postmenopausal women aged 40 75 years with an intact uterus, body mass index %32.2 kg/m 2, and no evidence of endometrial hyperplasia at screening were eligible for enrollment in the SMART-1 trial. Subjects were considered to be postmenopausal if they completed their last menstrual cycle at least 1 year before screening with serum FSH R30 miu/ml and 17b-estradiol %50 pg/ml. All subjects provided written informed consent before any study procedure was performed. Subjects were excluded if they had a history or presence of known or suspected estrogen-dependent neoplasia; known hypersensitivity to estrogens; thromboembolic disease, cerebrovascular event, or ischemic heart disease; history of breast cancer, melanoma, or any gynecologic cancer at any time; unresolved findings suggestive of malignant changes on the prestudy mammogram; certain unresolved or abnormal cervical smear results; or any endocrine disease except for controlled hypothyroidism. Subjects could not have used any oral estrogen-, progestin-, androgen-, or SERM-containing medication, or any vaginal or transdermal hormonal products within 8 weeks before screening, any investigational drug within 60 days, an intrauterine device within 12 weeks, or any injectable or pelleted hormone products within 24 weeks. The primary endpoint for the study was the incidence of endometrial hyperplasia at month 12 in the efficacy-evaluable population (EEP). To evaluate endometrial histology, endometrial biopsies were performed at screening and at months 6, 12, and 24, or when subjects withdrew from the study and more than 3 months had elapsed since their last assessment. Any subject who experienced prolonged or heavy uterine bleeding, or bleeding that occurred >3 months since the last biopsy also had an endometrial biopsy. All endometrial biopsy samples were centrally evaluated by two primary blinded pathologists using criteria and terminology previously described in the literature (10); hyperplasia was diagnosed if both primary pathologists agreed on the reading. Disagreement between pathologists was resolved by a blinded third pathologist, with the final diagnosis determined by the majority opinion. Any subject with a diagnosis of endometrial hyperplasia or carcinoma was withdrawn from the study and given appropriate evaluation and treatment. Transvaginal ultrasounds (TVUs) were performed to assess endometrial thickness, ovarian volume, and the presence of ovarian cysts, at approximately one third of the study sites at screening and at months 12 and 24. If at month 12 or 24 the TVU showed a nonmeasurable endometrium, endometrial double-walled thickness of >8 mm, or a focal abnormality, a hysteroscopy with directed biopsy was performed in place of the routine endometrial biopsy for that subject. The mean change from baseline in endometrial thickness, ovarian volume for each ovary, and the incidence of ovarian cysts were determined. The incidence of endometrial hyperplasia at any given time point was calculated as the number of subjects in the EEP with biopsies positive for endometrial hyperplasia at any time during the study up to and including the specified time point, divided by the number of subjects in the EEP with biopsies available at the specified time point plus all subjects in the EEP with biopsy samples positive for endometrial hyperplasia before the specified time point. The EEP included subjects who took at least one dose of the study drug; had an endometrial biopsy read by central pathologists at screening; had an endometrial biopsy performed on therapy for the specified time point 30 days; or received a diagnosis of hyperplasia at any prior time point. By analyzing this population, the incidence rates are reported from a smaller and more appropriate pool of patients than that with an intent-to-treat (ITT) population, resulting in a smaller denominator than with an ITT population, and a more conservative approach. Reporting incidence data using the EEP is customary in the medical literature (3, 11), as reporting on the ITT population could dilute the incidence rate. Sample size was calculated based on an acceptable rate of hyperplasia defined as an observed rate of %2% with a one-sided 95% upper confidence limit of %4%. With a sample size of 300 per group and a hyperplasia rate of approximately 1% at month 12, the probability of the observed rate exceeding 2% and the upper limit of the 95% one-sided confidence interval (CI) exceeding 4% was calculated to be approximately 0.05. For the primary analysis at month 12, a stepwise procedure was followed to control for the overall type I error rate because of multiple comparisons. In the first step, regimens with (40 or 20 mg) and the lower dose of CE (0.45 mg) were evaluated simultaneously using 97.5% one-sided CIs (to adjust for the dual comparison). If acceptable rates of endometrial hyperplasia were observed, then the / dose was evaluated using 95% CIs, as well as the three /CE doses containing 0.625 mg of CE using 95% CIs in a stepwise manner from the highest to lowest dose of combined with CE. If at any step, unacceptable rates of endometrial hyperplasia were found, the analysis was considered complete and rates for that regimen and all subsequent regimens were considered not acceptable. Stepwise procedures were not used for secondary analyses (endometrial hyperplasia at months 6 and 24). Comparisons of /CE regimens vs. placebo and vs. raloxifene were made with two-sided 95% CIs at months 6, 12, and 24. Comparisons with placebo for total double-walled endometrial thickness and ovarian volume (for each ovary) were made using an analysis of covariance (ANCOVA) model with treatment as a factor and baseline value as a covariate. The Fisher s exact test was used to evaluate between-group comparisons for the number and percentage of subjects with a double-walled thickness of >5mmor>8 mm, and a change from baseline of >3mmor>5 mm; and the incidence of endometrial polyps and proliferative endometrium. Adverse events (AEs) were defined as any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiologic observations that occurred in the clinical study subjects, regardless of causal relationship. Adverse events were coded using the Medical Dictionary for Regulatory Activities. The number and percentage of subjects experiencing each type of AE was summarized by body system for all AEs. Incidences for all AEs were compared among treatment groups for an overall P-value Fertility and Sterility â 1019

using c 2 analysis, and for each active treatment group compared with placebo using Fisher s exact test. RESULTS Of 10,511 subjects screened, 3,544 subjects were randomly assigned to a treatment group and 3,397 subjects took R1 dose of the study drug; 2,546 subjects (75%) were included in the EEP at 1 year. At 6 and 24 months, 2,835 and 2,191 subjects were analyzed, respectively. Further patient disposition is reported in Table 1. Demographic and baseline characteristics of the subjects are provided in Table 2. At month 12, the incidence of endometrial hyperplasia for all /CE doses was <1% (predefined acceptable limit was %2%), except for /CE (0.625 mg; Table 3). No hyperplasia was observed with /, (20 or 40 mg)/, raloxifene, and placebo. At month 6, no hyperplasia was observed for most /CE groups, except for /CE (0.625 mg; 1.61%) and /CE (0.625 mg; 0.28%). At month 24, hyperplasia rates with (20 or 40 mg)/ce (0.625 or 0.45 mg) remained <1%, whereas hyperplasia rates were 7.14% with /CE (0.625 mg) and 2.53% with /. Endometrial hyperplasia rates were similar to those with placebo or raloxifene for all doses of /CE except for /CE (0.625 mg) at all time points and / at month 24 (Table 4). In addition to the 32 subjects with endometrial hyperplasia who gave the incidences reported above, other clinically important endometrial biopsy findings included: [1] 1 endometrial hyperplasia identified during follow-up after month 24 (placebo); [2] two reports of endometrial malignancies read by one primary pathologist (one with [10 mg]/ce [0.625 mg] and one with placebo) with the second pathologist reading endometrial tissue other; and [3] one endometrial malignancy read by two pathologists ( [20 mg]/ce [0.45 mg]), the only incident that met the study criteria for malignancy. The single report of endometrial malignancy (identified by two pathologists) could not be confirmed following hysterectomy and sectioning of the entire endometrium. For (20 or 40 mg)/ce (0.625 or 0.45 mg), the adjusted mean ( SE) increases from baseline in endometrial thickness assessed by TVU were small (<1 mm) and not significantly different from that with placebo or raloxifene, respectively, at month 12 (0.37 0.21, 0.37 0.21) or month 24 (0.02 0.26, 0.16 0.25). However, at months 12 and 24, respectively, significant increases (P < 0.01) in endometrial thickness were observed with /CE (0.625 mg; 2.54 0.2, 2.15 0.24) and /CE (0.45 mg ;1.23 0.2, 1.91 0.24) compared with placebo and raloxifene. Across /CE treatment groups, the number of subjects with an increase from baseline in endometrial thickness of >3 mm or >5 mm at any time during therapy was statistically similar to placebo (n ¼ 5 and 4, respectively), except for /CE (0.625 mg;n ¼ 49 and 33, respectively) and /CE (0.45 mg; n ¼ 28 and 15, respectively; P < 0.05). The number of subjects with an increase from baseline in endometrial thickness >3 mm or >5 mm ranged from 1 15 for the remaining /CE groups. A similar pattern was observed for the number of subjects with endometrial thickness of >5 mmor>8 mm at any time on therapy. The percentage of subjects with a proliferative endometrium was highest with /CE (0.625 or 0.45 mg) and tended to attenuate with increasing dose. Differences from placebo were significant for /CE (0.625 or 0.45 mg; P < 0.001) at months 6, 12, and 24, and at some time points for / CE (0.625 or 0.45 mg; P < 0.05). The incidence of endometrial polyps at baseline ranged from approximately 1.0% to 4.0%; no clear /CE dose trends were observed in the cumulative incidence of endometrial polyps through month 24. Generally, the incidence of endometrial polyps with /CE groups was similar to that with placebo (1.3 1.6%) at all time points, except at month 24 with /CE (0.625 mg; 6.25%; P < 0.01) and /CE (0.45 mg; 5.67%; P < 0.05). The incidences of endometrial polyps in these two groups at month 24 and / at month 12 (3.6%) were also significantly different (P < 0.05) vs. raloxifene at month 12 (1.0%) and month 24 (1.5%). TABLE 1 Subject disposition. Raloxifene (60 mg) Placebo Received R1 dose 430 414 417 430 433 423 423 427 of study medication Excluded from EEP 87 100 105 109 97 114 125 114 analysis EEP analyzed 343 314 312 321 336 309 298 313 Discontinuations, n (%) 136 (31.6) 130 (31.4) 136 (32.6) 141 (32.8) 129 (29.8) 142 (33.6) 151 (35.7) 151 (35.4) Adverse event 66 (15.3) 52 (12.6) 49 (11.8) 63 (14.7) 46 (10.6) 43 (10.2) 59 (13.9) 61 (14.3) Subject request 28 (6.5) 36 (8.7) 39 (9.4) 32 (7.4) 34 (7.9) 34 (8.0) 36 (8.5) 33 (7.7) Other event 15 (3.5) 26 (6.3) 16 (3.8) 26 (6.0) 22 (5.1) 25 (5.9) 22 (5.2) 19 (4.4) Failed to return 17 (4.0) 8 (1.9) 20 (4.8) 14 (3.3) 18 (4.2) 24 (5.7) 22 (5.2) 13 (3.0) Protocol violation 8 (1.9) 6 (1.4) 7 (1.7) 5 (1.2) 5 (1.2) 7 (1.7) 3 (0.7) 12 (2.8) Unsatisfactory response a 2 (0.5) 1 (0.2) 4 (1.0) 1 (0.2) 4 (0.9) 8 (1.9) 9 (2.1) 12 (2.8) Death 0 1 (0.2) 1 (0.2) 0 0 1 (0.2) 0 1 (0.2) Completed, n (%) 294 (68.4) 284 (68.6) 281 (67.4) 289 (67.2) 304 (70.2) 281 (66.4) 272 (64.3) 276 (64.6) a P < 0.01. Pickar. Effects of /CE on the endometrium. Fertil Steril 2009. 1020 Pickar et al. Effects of /CE on the endometrium Vol. 92, No. 3, September 2009

Fertility and Sterility â 1021 TABLE 2 Subject demographic and baseline characteristics. a Characteristic Raloxifene (60 mg) Placebo Age (years) n 343 314 312 321 336 309 298 313 Mean SD 56.27 5.52 56.33 5.81 56.65 5.81 56.69 5.86 56.08 5.62 56.75 5.88 56.43 5.62 56.55 6.15 Ethnic origin, n (%) White 284 (82.80) 260 (82.80) 254 (81.41) 257 (80.06) 267 (79.46) 235 (76.05) 238 (79.87) 244 (77.96) Black 48 (13.99) 46 (14.65) 42 (13.46) 47 (14.64) 46 (13.69) 54 (17.48) 44 (14.77) 53 (16.93) Hispanic 8 (2.33) 6 (1.91) 11 (3.53) 8 (2.49) 17 (5.06) 11 (3.56) 8 (2.68) 11 (3.51) Other 0 0 1 (0.32) 0 1 (0.30) 3 (0.97) 2 (0.67) 2 (0.64) BMI (kg/m 2 ) Mean SD 25.73 3.50 25.87 3.53 25.80 3.18 25.87 3.34 25.9 3.40 25.78 3.42 25.87 3.27 25.96 3.51 Years since last menstrual period Mean SD 7.71 5.56 7.98 5.46 8.14 5.65 7.95 5.60 7.97 5.53 8.25 5.91 8.20 5.80 8.42 6.01 Age at last menstrual period Mean SD 49.08 4.36 48.87 4.55 48.98 4.37 49.22 4.63 48.62 4.06 49.01 3.91 48.73 4.51 48.61 4.77 Note: BMI ¼ body mass index. a Numbers of subjects in each group are based on the efficacy evaluable population for the primary efficacy analysis of incidence of endometrial hyperplasia. Pickar. Effects of /CE on the endometrium. Fertil Steril 2009.

TABLE 3 Incidence (%) of endometrial hyperplasia at month 12. n [ 341 n [ 314 n [ 311 n [ 320 n [ 336 n [ 309 Total cases (%) 13 (3.81) a 1 (0.32) 0 (0.00) 3 (0.94) 0 (0.00) 0 (0.00) 95% CI (%) b 2.27 5.99 a 0.02 1.50 0.00 0.96 0.26 2.41 0.00 1.09 c 0.00 1.19 c Note: No hyperplasia was observed with placebo or raloxifene at month 12. a Hyperplasia rate is not acceptable per study criteria. b One-sided 95% CI. c One-sided 97.5% CI per stepwise procedure to adjust for simultaneous comparisons ( [20 and 40 mg] combined with CE [0.45 mg]). Pickar. Effects of /CE on the endometrium. Fertil Steril 2009. For all /CE doses, TVU demonstrated only minimal changes in ovarian volume through month 24, with no significant betweengroup differences. Ovarian cysts of diameter R20 mm were identified in 18 subjects and were distributed similarly among groups (data not shown). The incidence of treatment-emergent AEs was not significantly different among treatment groups (P ¼ 0.696). Adverse events were reported as a primary or secondary reason for study discontinuation by 10.6 15.6% of subjects across /CE groups compared with 14.5% in placebo and 14.2% in raloxifene groups. The rate of study withdrawal because of endometrial hyperplasia AEs was highest with /CE (0.625 mg; 2.6%) compared with any other group (0 0.9%; P < 0.001). The incidence of urogenital system AEs is summarized in Table 5. There were significant overall differences among groups in the percentage of subjects with any (one or more) endometrial AEs (P < 0.001). This finding was attributed to significantly higher incidences of any endometrial event reported with /CE (0.625 mg; 4.9%; P < 0.001) and /CE (0.45 mg; 2.3%; P < 0.001) vs. placebo (0.5%). In addition, the incidence of endometrial hyperplasia was significantly higher (3.7%; P < 0.001) with /CE (0.625 mg) compared with placebo (0%). Overall, the incidence of any ovarian or cervical event was not significantly different among treatment groups (Table 5). The incidences of ovarian cyst, cervical inflammation, abnormal cervical smear, cervical dysplasia, cervical polyp, and cervical disorder were similar across groups. One case each of ovarian carcinoma was reported for subjects treated with /CE (0.625 mg; detected on study day 534) and 10 mg/ce 0.45 mg (detected on study day 182). DISCUSSION In this study, the TSEC containing /CE had an acceptable endometrial profile, suggesting an alternative to the addition of a progestin to estrogens for endometrial protection. When combined with either CE (0.625 or 0.45 mg), was the lowest effective dose that prevented endometrial hyperplasia. These data also show that this TSEC had a favorable safety profile in regard to the incidence of endometrial AEs. Endometrial protection with plus CE (0.625 or 0.45 mg) might contribute to the evolution of new therapies for postmenopausal women. The lowest effective dose of that protected the endometrium from the stimulatory effects of CE (0.45 and 0.625 mg) was 20 mg, TABLE 4 Differences in the incidence of endometrial hyperplasia at months 12 and 24 (efficacy evaluable population). Time (mo) Difference from placebo 12 n ¼ 341 n ¼ 314 n ¼ 311 n ¼ 320 n ¼ 336 n ¼ 309 Rate (%) SE 3.81 1.04 a 0.32 0.32 0.00 0.00 0.94 0.54 0.00 0.00 0.00 0.00 95% CI 1.78 5.85 a 0.31 0.94 0.00 0.00 0.12 2.00 0.00 0.00 0.00 0.00 24 n ¼ 294 n ¼ 271 n ¼ 267 n ¼ 277 n ¼ 293 n ¼ 268 Rate (%) SE 7.14 1.50 a 0.74 0.52 0.00 0.00 2.53 0.94 a 0.34 0.34 0.00 0.00 95% CI 4.19 10.09 a 0.28 1.76 0.00 0.00 0.68 4.38 a 0.33 1.01 0.00 0.00 Difference from raloxifene 12 n ¼ 341 n ¼ 314 n ¼ 311 n ¼ 320 n ¼ 336 n ¼ 309 Rate (%) SE 3.81 1.04 a 0.32 0.32 0.00 0.00 0.94 0.54 0.00 0.00 0.00 0.00 95% CI 1.78 5.85 a 0.31 0.94 0.00 0.00 0.12 2.00 0.00 0.00 0.00 0.00 24 n ¼ 294 n ¼ 271 n ¼ 267 n ¼ 277 n ¼ 293 n ¼ 268 Rate (%) SE 7.14 1.50 a 0.74 0.52 0.00 0.00 2.53 0.94 a 0.34 0.34 0.00 0.00 95% CI 4.19 10.09 a 0.28 1.76 0.00 0.00 0.68 4.38 a 0.33 1.01 0.00 0.00 a Differences are statistically significant (95% CIs do not include 0.00). Pickar. Effects of /CE on the endometrium. Fertil Steril 2009. 1022 Pickar et al. Effects of /CE on the endometrium Vol. 92, No. 3, September 2009

TABLE 5 Incidence of urogenital adverse events. Adverse event, n (%) Raloxifene (60 mg) Placebo (MedDRA term) n [ 430 n [ 414 n [ 417 n [ 430 n [ 433 n [ 423 n [ 423 n [ 427 Any endometrial event a 21 (4.9) c 4 (1.0) 5 (1.2) 10 (2.3) b 8 (1.8) 2 (0.5) 1 (0.2) 2 (0.5) Endometrial disorder 1 (0.2) 0 (0.0) 0 (0.0) 2 (0.5) 0 (0.0) 1 (0.2) 0 (0.0) 0 (0.0) Endometrial hyperplasia a 16 (3.7) b 1 (0.2) 0 (0.0) 4 (0.9) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Endometrial hypertrophy 0 (0.0) 0 (0.0) 1 (0.2) 1 (0.2) 0 (0.0) 0 (0.0) 1 (0.2) 0 (0.0) Uterine Polyp 5 (1.2) 4 (1.0) 4 (1.0) 3 (0.7) 8 (1.8) 1 (0.2) 0 (0.0) 2 (0.5) Any ovarian event 2 (0.5) 1 (0.2) 4 (1.0) 3 (0.7) 2 (0.5) 2 (0.5) 1 (0.2) 1 (0.2) Ovarian cyst 2 (0.5) 1 (0.2) 4 (1.0) 3 (0.7) 2 (0.5) 2 (0.5) 1 (0.2) 1 (0.2) Any cervical event 22 (5.1) 21 (5.1) 11 (2.6) 17 (4.0) 23 (5.3) 16 (3.8) 19 (4.5) 18 (4.2) Cervicitis 2 (0.5) 1 (0.2) 0 (0.0) 1 (0.2) 2 (0.5) 1 (0.2) 0 (0.0) 1 (0.2) Smear cervix abnormal 20 (4.7) 18 (4.3) 8 (1.9) 11 (2.6) 20 (4.6) 13 (3.1) 18 (4.3) 14 (3.3) Cervical dysplasia 0 (0.0) 0 (0.0) 1 (0.2) 0 (0.0) 2 (0.5) 0 (0.0) 0 (0.0) 1 (0.2) Cervical polyp 2 (0.5) 2 (0.5) 3 (0.7) 5 (1.2) 2 (0.5) 0 (0.0) 1 (0.2) 2 (0.5) Cervix disorder 0 (0.0) 1 (0.2) 0 (0.0) 1 (0.2) 0 (0.0) 2 (0.5) 0 (0.0) 1 (0.2) Note: MedDRA ¼ Medical Dictionary for Regulatory Activities. a P < 0.001 (overall P value, c 2 analysis). b P < 0.05 vs. placebo. c P < 0.001 vs. placebo. Pickar. Effects of /CE on the endometrium. Fertil Steril 2009. as indicated by acceptable rates of endometrial hyperplasia after 1 year (primary endpoint) and 2 years of exposure. In contrast, TSECs that included with CE (0.625 or 0.45 mg) exhibited unacceptable levels of endometrial hyperplasia. Rates of endometrial hyperplasia with CE alone have ranged from 6.58% with 0.45 mg CE to 10.45% with 0.625 mg CE at 12 months, and 14.93% with 0.45 mg to 27.27% with 0.625 mg at 24 months (12). In our study, prevented such rates of endometrial hyperplasia observed with CE alone. In addition to acceptably low rates of endometrial hyperplasia with /CE, endometrial safety was suggested by endometrial thickness comparable to that with placebo for most /CE doses. In particular, changes from baseline in endometrial thickness observed with /CE (0.625 or 0.45 mg) were similar to those with placebo at month 12 or 24. This study also found minimal changes in ovarian volume that were similar between groups, and ovarian cysts reports that were distributed similarly among groups. Additionally, ovarian and cervical AEs were also similar across groups including placebo, and rates of study discontinuation due to an AE were similar between /CE groups and compared with placebo or raloxifene. Endometrial hyperplasia, an accepted surrogate marker for endometrial cancer, was used in this study to monitor endometrial safety. Endometrial safety was examined using endometrial hyperplasia rates as described in previously randomized, double-blind, placebocontrolled trials evaluating the endometrial safety of currently approved hormone therapies containing MPA and CE doses similar to those in this report (3, 11). In the Women s Health, Osteoporosis, Progestin, Estrogen (HOPE) study, lower doses of MPA adequate to prevent endometrial hyperplasia observed with lower doses of CE were determined, and the endometrial safety of /MPA (2.5 mg) was confirmed (11). Since then, the large, randomized, placebo-controlled Women s Health Initiative found no increase in risk for endometrial cancer with /MPA (2.5 mg) (13), confirming the use of endometrial hyperplasia as a surrogate marker for endometrial cancer. In our study, the methodology for monitoring and evaluating endometrial hyperplasia was also the same as that used in the Women s HOPE study (11). Furthermore, study rigor was demonstrated by inclusion of a placebo control, as well as the active control, raloxifene, as a reference for nonhyperplastic endometrium. Our study is the first randomized, double-blind, placebo-controlled trial to report an acceptable endometrial safety profile with a TSEC containing /CE in postmenopausal women with an intact uterus. This study examined relevant endometrial endpoints with various doses of with CE (0.625 or 0.45 mg), and determined the lowest effective dose for endometrial safety with this regimen. We reported incidences of endometrial hyperplasia with (20 mg)/ce (0.625 or 0.45 mg) of <1% for up to 2 years. These rates were similar to those found with MPA combined with similar doses of CE (<1%) (11), suggesting endometrial safety with /CE comparable to that reported with currently prescribed hormone therapies. In conclusion, findings from this phase 3 SMART-1 trial indicate that a TSEC composed of /CE has an acceptable endometrial safety profile. Thus, delivered with CE appears to be an acceptable approach to protecting the endometrium in place of adding a progestin to estrogen therapy. The beneficial effects of /CE on menopausal symptoms and bone loss, as well as the bleeding profile and overall safety data, are reported in separate publications in this journal issue (14 16). This study is the first to describe endometrial protection with therapeutic components that exert their effects through the estrogen receptor. Our data on the use of /CE in menopausal women are promising as novel comprehensive menopausal therapies evolve. Acknowledgments: We acknowledge Keqin Qi and David Qu for statistical analyses and related programming, respectively, and Kathleen Ohleth, Ph.D., for collaboration in preparing the manuscript. A full list of the participating investigators and study sites has been published elsewhere (14). Fertility and Sterility â 1023

REFERENCES 1. Smith DC, Prentice R, Thompson DJ, Herrmann WL. Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 1975;293:1164 7. 2. Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 1975;293:1167 70. 3. Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. The Menopause Study Group. Am J Obstet Gynecol 1994;170:1213 23. 4. Stovall DW, Utian W, Gass M, Qu Y, Muram D, Wong M, et al. The effects of combined raloxifene and oral estrogen on vasomotor symptoms and endometrial safety. Menopause 2007;14:510 7. 5. Davis SR, O Neill SM, Eden J, Baber R, Ekangaki A, Stocks JM, et al. Transition from estrogen therapy to raloxifene in postmenopausal women: effects on treatment satisfaction and the endometrium-a pilot study. Menopause 2004;11:167 75. 6. Komm BS, Lyttle CR. Developing a SERM: stringent preclinical selection criteria leading to an acceptable candidate (WAY-140424) for clinical evaluation. Ann N Y Acad Sci 2001;949:317 26. 7. Komm BS, Kharode YP, Bodine PV, Harris HA, Miller CP, Lyttle CR. Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology 2005;146:3999 4008. 8. Ronkin S, Northington R, Baracat E, Nunes MG, Archer DF, Constantine G, et al. Endometrial effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal women. Obstet Gynecol 2005;105:1397 404. 9. Crabtree JS, Peano BJ, Zhang X, Komm BS, Winneker RC, Harris HA. Activity of three selective estrogen receptor modulators on hormone-dependent responses in the mouse uterus and mammary gland. Mol Cell Endocrinol 2008;287:40 6. 10. Kurman RJ, Norris HJ. Endometrial hyperplasia and related cellular changes. In: Kurman RJ, ed. Blaustein s pathology of the female genital tract. New York: Springer-Verlag, 1994:411 37. 11. Pickar JH, Yeh I, Wheeler JE, Cunnane MF, Speroff L. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001;76:25 31. 12. Pickar JH, Yeh IT, Wheeler JE, Cunnane MF, Speroff L. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results. Fertil Steril 2003;80:1234 40. 13. Anderson GL, Judd HL, Kaunitz AM, Barad DH, Beresford SA, Pettinger M, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women s Health Initiative randomized trial. JAm Med Assoc 2003;290:1739 48. 14. Lobo RA, Pinkerton JV, Gass MLS, et al. Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile. Fertil Steril 2009;92:1025 38. 15. Lindsay R, Gallagher JC, Kagan R, Pickar JH, Constantine G. Efficacy of tissue-selective estrogen complex (TSEC) ofbazedoxifene/conjugated estrogens (/CE) for osteoporosis prevention in at-risk postmenopausal women. Fertil Steril 2009;92:1045 52. 16. Archer DF, Lewis V, Carr BR, Olivier S, Pickar JH. Bazedoxifene/conjugated estrogens (/CE): incidence of uterine bleeding in postmenopausal women. Fertil Steril 2009;92:1039 44. 1024 Pickar et al. Effects of /CE on the endometrium Vol. 92, No. 3, September 2009